1. Field of the Invention
Novel 2-substituted and 2,6-disubstituted penem compounds are prepared by totally synthetic chemical processes and found to be potent .beta.-lactam antibiotics.
2. Description of the Prior Art
Penicillins and cephalosporins comprise a group of well-known antibacterial agents commonly grouped together as a class called .beta.-lactam antibiotics. Most of the work in this field has been done, broadly speaking, with 6-aminopenicillanic acid (6-APA), 7-aminocephalosporanic acid (7-ACA) and derivatives thereof produced by fermentation or chemical transformation of the natural products. Despite the extensive progress made in preparing active derivatives of 6-APA and 7-ACA, there is a continuing search for synthetic and semi-synthetic routes to new families of .beta.-lactam antibiotics which may possess more advantageous properties than those derived from the known penicillin and cephalosporin nuclei.
Considerable work has been done on total chemical synthesis of both known .beta.-lactams and nuclear analogs of such knowm compounds. Literature publications relating to non-conventional bicyclic .beta.-lactams include the following:
(a) Belgian Pat. No. 846,933 discloses the compound of the formula ##STR2## which has been isolated from fermentation of Streptomyces clavuligerus. This compound, named clavulanic acid, possesses a low order of antibacterial activity but inhibits the action of certain .beta.-lactamases and reportedly enhances the in vitro and in vivo activity of some penicillins and cephalosporins.
(b) U.K. Pat. No. 1,467,413 discloses the fermentation product having the formula ##STR3## which is reported to possess some antibacterial activity and to be a .beta.-lactamase inhibitor.
(c) Brown, et al. in J.C.S, Chem. Comm., 359-360 (1977) disclose preparation of the compound of the formula ##STR4## There is no indication from the publication that the compound possesses any antibacterial activity.
(d) Eglington in J.C.S. Chem. Comm., 720 (1977) discloses preparation of the ester of the formula ##STR5## The compound is reported to be a weak inhibitor of .beta.-lactamases.
(e) U.S. Pat. No. 3,950,357 describes a fermentation process for producing thienamycin, the compound of the formula ##STR6## Thienamycin is reported to be a highly potent broad-spectrum antibiotic.
(f) Belgian Pat. No. 849,118 (equivalent U.S. Pat. No. is 4,118,566) discloses a series of 6-amino-2-penem-3-carboxylic acid derivatives of the formula ##STR7## wherein R.sub.1.sup.a is hydrogen or an N-protecting group, R.sub.1.sup.b is hydrogen or acyl (or R.sub.1.sup.a and R.sub.1.sup.b taken together are a divalent N-protecting group), --CO--R.sub.2 is carboxyl or a protected carboxyl group and R.sub.3 is hydrogen or a C-bonded organic group. The compounds and their salts are said to possess antibacterial activity. No compounds are disclosed which do not contain the amino or acylamido moiety at the 6-position of the .beta.-lactam ring.
(g) Acta Pharmaceutica Suecica, 14 (Suppl.), 23-25 (1977) discloses 2,6-disubstituted penems of the formula ##STR8## and reports such penems to be considerably less active than the penicillin and cephalosporin analogs. Also disclosed as antibacterial agents (again without definition of R) are 2-substituted penems of the formula ##STR9##
(h) Annual Reports in Medicinal Chemistry, 13, 239-248 (1978) discloses the unsubstituted penem of the formula ##STR10## as having no .beta.-lactamase inhibitory activity.
(i) South African Patent 77/6594 discloses 1-carba-2-penem-3-carboxylic acids of the formula ##STR11## wherein R.sup.1, R.sup.2 and R.sup.3 are independently selected from the group consisting of hydrogen, substituted and unsubstituted; alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heterocycyl and heterocycylalkyl wherein the substituent or substituents relative to the above-named radicals are selected from the group consisting of amino, hydroxy, alkoxyl, mercapto, alkylthio, arylthio, sulfamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro, cyano and carboxy and wherein the hetero atom in the above-named heterocyclic moiety is selected from the group consisting of oxygen, nitrogen and sulfur. The compounds are reported to have antibiotic activity.
(j) Belgian Pat. No. 866,845 discloses 2-penem compounds of the formula ##STR12## wherein R.sub.1 =hydrogen or an organic radical (bonded to the ring carbon atom via a carbon atom) or an etherified mercapto group and R.sub.2 is hydrogen or a group R.sub.2.sup.A which forms with CO a protected carboxylic group. The disclosed compounds are reported to be antibacterial agents and .beta.-lactamase inhibitors.